This proposal is centered on the synthesis of cross-bridged tetraamine ligands and the evaluation of their efficacy as carriers of cancer diagnostic and therapeutic copper, gallium, and indium radionuclides. We propose to address the hypothesis that cross-bridged tetraamines will form kinetically inert complexes with copper radionuclides, endowing them with greater in vivo stability than the traditionally used macrocycles such as Cyclam or TETA. Additionally, we propose that this same class of chelators will also form highly kinetically stable complexes with gallium and indium radionuclides. Both goals will further advance the development of radiometal-labeled complexes as radiopharmaceuticals. The three specific aims of this proposal are: (I) to synthesize new ionizable chelators based on the cross-bridged tetraamine motif and investigate the formation and stability of their copper coordination complexes; (II) to prepare Cu64 complexes of these cross-bridged chelators and perform biological studies to gauge their viability as radiopharmaceutical carriers; and (III) to carry out parallel chemical and biological studies on the gallium and indium complexes of these chelators. In Specific Aim (I), pendant-arms containing ionizable carboxylate, phosphonate, and aryloxide functions will be attached to the parent cross-bridged tetraamines Cyclam and Cyclen using standard organic synthetic methodology. Metal binding chemistry of these ligands will be carried out and resulting complexes characterized spectrally and structurally. The kinetic and redox stability, and thermodynamic stability constant of each representative complex will then be determined to identify promising ligand candidates for follow-up biological studies. For Specific Aims (II) and (III), selected cross-bridged ligands will be labeled with Cu, Ga, and In radionuclides and examined for their in vivo biostability and biodistribution behavior. The most promising of these will be attached to bifunctional conjugates of the somatostatin analog, tyrosine3-octreotate (Y3-TATE) to evaluate the in vivo efficacy of these as a cancer diagnostic and/or therapeutic radiopharmaceutical.